key: cord-0920156-biki2nam
authors: Herrera, Joseph E.; Niehaus, William N.; Whiteson, Jonathan; Azola, Alba; Baratta, John M.; Fleming, Talya K.; Kim, Soo Yeon; Naqvi, Huma; Sampsel, Sarah; Silver, Julie K.; Gutierrez, Monica Verduzco; Maley, Jason; Herman, Eric; Abramoff, Benjamin
title: Multidisciplinary collaborative consensus guidance statement on the assessment and treatment of fatigue in postacute sequelae of SARS‐CoV‐2 infection (PASC) patients
date: 2021-08-24
journal: PM R
DOI: 10.1002/pmrj.12684
sha: 64474d7896e3adaa3b53d1944d16ddb2f95232aa
doc_id: 920156
cord_uid: biki2nam

nan

Large numbers of individuals who have been infected with SARS-CoV-2, the virus responsible for COVID-19, continue to experience a constellation of symptoms long past the time that they have recovered from the acute stages of their illness. Often referred to as "long COVID," these symptoms, which can include fatigue, shortness of breath, palpitations, cognitive dysfunction ("brain fog"), sleep disorders, fevers, gastrointestinal symptoms, anxiety, depression, and others, can persist for months and can range from mild to incapacitating. Although still being defined, these effects can be collectively referred to as postacute sequelae of SARS-CoV-2 infection (PASC). 1 The magnitude of this problem is not yet known, but given the millions of individuals worldwide who have had, or will have, COVID-19, the societal impacts are likely to be profound and long lasting. [2] [3] [4] [5] It is widely acknowledged that systematic study is needed to develop an evidence-based approach for caring for patients with PASC. At present, there is a dearth of rigorous scientific evidence regarding effective assessment and treatment of PASC that prevents the creation of evidence-based clinical guidelines. However, the U.S. health system is currently seeing an increase in the number of patients presenting with PASC, and there is an urgent need for clinical guidance in treating these patients. The goal of this, and future statements, is to provide practical guidance to clinicians in the assessment and treatment of patients presenting with PASC. This Consensus Guidance Statement on fatigue is the first of a series focused on the most prominent PASC symptoms.

The American Academy of Physical Medicine and Rehabilitation (AAPM&R) Multi-Disciplinary PASC Collaborative ("PASC Collaborative") was created, in part, to develop expert recommendations and guidance from established PASC centers with extensive experience in managing patients with PASC. The PASC Collaborative is following an iterative, development approach to achieve consensus on assessment and treatment recommendations for a series of Consensus Guidance Statements focused on the most prominent PASC symptoms. These statements were developed by a diverse team of experts, with input from patient representatives with a history of PASC, and integrate current experience and expertise with available evidence to provide tools to clinicians treating patients. There is an intentional focus on health equity as disparities in care and outcomes are critically important to address. Beyond patient care, the hope is that a broadened understanding of current patient care practices will help identify areas of future research. A full description of the methodology is also published in this issue. 6 We acknowledge that the definition of PASC is evolving, and there are various factors that contribute to diagnosis. The PASC Collaborative sought input from patient representatives with a history of PASC and patient-led research initiatives to inform recommendations. For example, previous literature has suggested that PASC be defined as the continuation of symptoms beyond 3 or 4 weeks from the onset of acute infection. 7 Other definitions of PASC include symptoms lasting longer than 3 months. 8 Based on feedback of patient representatives that earlier evaluation, diagnosis, and management can improve access to beneficial interventions, for the purpose of this Consensus Guidance Statement, we recommend expanded assessment if symptoms are not improving 1 month after acute symptom onset.

These Consensus Guidance Statements are intended to reflect current practice in patient assessment, testing, and treatments. They should not preclude clinical judgment and must be applied in the context of the specific patient, with adjustments for patient preferences, comorbidities, and other factors.

Fatigue is a feeling of weariness, tiredness, or lack of energy. It can be physical, cognitive, or emotional, mild to severe, intermittent to persistent, and affect a person's energy, motivation, and concentration. Fatigue can negatively affect an individual's sense of well-being and quality of life and generally lacks objective markers. Fatigue during an acute viral illness is common; however individuals with PASC are often presenting with long lasting and debilitating fatigue after recovery from their acute viral illness. 5 Further discussion on the definition and impact of fatigue can be found in the Institute of Medicine's 2015 report on chronic fatigue syndrome (Chapter 4). 9 Individuals are seeking care from their clinicians for fatigue following COVID-19. Among nonhospitalized adults with a history of COVID-19 and enrolled in an integrated health system in Georgia, approximately two thirds had at least one outpatient medical encounter between 1 and 6 months after their diagnosis. 10 Approximately two thirds of these patients received a new primary diagnosis, with fatigue being one of the most common based on International Classification of Diseases, Tenth Revision codes. 10 In another study describing the long-term health consequences for individuals hospitalized with COVID-19, the most common symptoms were fatigue or muscle weakness (63%) and sleep difficulties (26%). 11 Anxiety and depression were also common, reported by 23% of patients. Greater than 20% of patients had performances on the 6-minute walk test below the lower-limit of normal. 11 The Patient Led Research Collaborative, a selforganized group of individuals with PASC who conduct patient-led research around the long COVID experience, conducted a study of self-reported symptoms of individuals enrolled in support groups for PASC. 12 A majority (96%) of individuals who completed the survey selfidentified as having PASC reported symptoms beyond 90 days. The most common early symptoms were fatigue, cough, shortness of breath, headaches, muscle aches, chest tightness, and sore throat. The most frequent symptoms reported after 6 months were fatigue, postexertional malaise, and cognitive dysfunction. Greater than 85% of individuals experienced relapses of their symptoms, with exercise, physical or mental activity, and stress being the main triggers. In addition, 42.5% reported requiring a reduced work schedule compared to pre-illness and 22.3% were not working at the time of survey because of their health conditions. 12

Fatigue is among the most common persistent symptoms following COVID-19 in both individuals that have been hospitalized (p = 24.6%, confidence interval [CI] 20. 11-29.72 ) and those that have not been hospitalized (p = 37.1%, CI 26.54-49.06). 13 Although fatigue likely improves over time, it can persist beyond 6 months. 2, 5, 7 As noted in the PASC Collaborative methodology, 6 the recommendations that follow are based on expert consensus. Specific guidance recommendations that have been approved by consensus will be noted in the tables and recommendations will be followed by additional discussion (Table 1) .

It is not unusual for individuals to have persistent and fluctuating fatigue during their recovery from acute COVID-19 disease, particularly in the first 1 to 2 months. This fatigue can involve both physical and cognitive components. This document focuses on physical fatigue and a subsequent Consensus Guidance Statement will focus on cognitive issues. Additional assessment and management of post-COVID fatigue should be considered if a patient is not continuing to improve after the initial 4 weeks beyond symptom onset, if symptoms are severe, or if the patient is experiencing negative impacts on quality of life. In cases of mild fatigue that is not functionally limiting, it can be monitored for improvement as part of the natural recovery from COVID-19.

Common descriptions of PASC-related fatigue include:

• Severe exhaustion after minimal physical or mental exertion • The sense of being weighed down all day • After having a "good day" of increased activity level, the feeling of "crashing" requiring several days of recovery • Persistent tiredness or exhaustion after sleep/upon waking A wide differential for central and contributing factors to PASC-related fatigue should be considered (Table 2) . This differential may be affected by the severity of initial illness with those critically ill being at risk for postintensive care syndrome (PICS). Potential contributions to PICS-related fatigue include circadian rhythm disorders, critical illness polyneuropathy and myopathy, and mood disorders. 14 17 In patients presenting with fatigue, it is important to consider the evaluation of fatigue and diminished activity tolerance as related but distinct conditions. As these two symptoms may intersect, the differential etiologies of fatigue should be considered in conjunction with a separate differential for lowered activity tolerance. Patients should be evaluated for conditions that may exacerbate fatigue symptoms and warrant further testing and potential subspecialty referral (see Table 2 ). Particular areas include: • Sleep • Mood, including anxiety, depression and PTSD. Note: Patients often report dissatisfaction with their care because of their persistent symptoms being attributed to psychological factors. It is important to note that mood disorders may be secondary to persistent medical issues or one of many factors leading to fatigue.

A medication review should be conducted to investigate medications that may be contributing to fatigue. Of note, antihistamine, anticholinergic, and antidepressant/anxiolytic medications can contribute to fatigue in patients with PASC. 6 The following basic lab workup should be considered in new patients or those without lab workup in the 3 months before visit including complete blood count with differential, chemistries including renal and hepatic function tests, thyroid stimulating hormone, c-reactive protein or erythrocyte sedimentation rate, and creatinine kinase. Other laboratory tests may be considered based on the results of these tests or if there is specific concern for comorbid conditions as outlined in Table 2 .

Abbreviations: PASC, postacute sequelae of SARS-CoV-2 infection; PTSD, posttraumatic stress disorder.

When evaluating the etiology of fatigue, the following should be considered as central or contributing factors: sleep disorders, endocrine disorders, nutritional disorders, chronic infectious disorders, autoimmune/inflammatory disorders, cardiac disorders, respiratory disorders, psychiatric disorders, malignancies, drug reactions, and adultonset metabolic disorders (See Table 2 ).

Diminished activity tolerance is the inability or reduced ability to perform physical activity at the normally expected frequency, intensity level, or duration for people of that age, size, gender, and muscle mass. Individuals may experience unusually severe postexercise pain, fatigue, nausea, vomiting, or other negative effects. When evaluating the etiology of diminished activity tolerance, the following disorders or system dysfunctions should be considered as central or contributing factors: pulmonary, cardiovascular, and/or neuromuscular systems.

The presentation of fatigue in individuals with PASC may appear similar to myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). ME/CFS is a complex syndrome that often occurs following viral illness. A 2015 Institute of Medicine report on ME/CFS created specific diagnostic criteria as outlined in Table 3 . 9 The specific pathophysiology behind ME/CFS has yet to be discovered. The Centers for Disease Control and Prevention has developed treatment recommendations for ME/CFS that have been used to help develop the current treatment recommendations for PASC-related fatigue. 18 However, more data are needed to understand if and in which individuals PASC-related fatigue is a manifestation of ME/CFS and in which individuals PASCrelated fatigue represents a distinct process.

Finally, it is important to note that the etiology of fatigue may be multifactorial in individuals with PASC and there may not be one unifying cause of PASCrelated fatigue.

As with any treatment plan, clinicians treating patients with PASC-related fatigue are encouraged to discuss the unknowns of PASC treatments, as well as the pros and cons of any therapeutic approach. It may also be helpful to discuss that despite the unknown time course of post-COVID symptoms, it is the experience of established PASC centers that fatigue tends to slowly improve over time. As treatment is initiated, patients should be followed for their response to treatment and impact of treatment on level of function.

As with the PASC patient assessment, therapeutic options vary and should be customized based on history, comorbidities, and treatment response to date. It is important to note that if specific etiologies of fatigue are identified (see Table 2 ), they should be addressed as part of the treatment plan (Table 4 , Recommendation #4).

The current recommendations are based on the experience of the PASC Collaborative clinics and have helped to alleviate symptoms in cases in which specific contributing etiologies have not been identified or, despite addressing, symptoms persist. Additional details on techniques used by clinicians are summarized next. As treatment efficacy of therapeutic options emerges, these recommendations will be reviewed and revised on a periodic basis.

Begin an individualized and structured phased return to activity program An individually titrated, symptom-guided program of return to activity is recommended for patients presenting with fatigue. The goal of a rehabilitation program is to restore patients to previous levels of activity and improve quality of life. Until those goals have been achieved, the rehabilitation program should not focus on high intensity aerobic exercises or heavy weightlifting to build strength and endurance. If the rehabilitation program is advanced too quickly or is too intense, it may worsen symptoms and lead to postexertional malaise (PEM), a diagnostic criterion of ME/CFS. 9 The titrated approach encourages patients to perform activities at a submaximal level to avoid exacerbation of fatigue and PEM. Activity should be adjusted in response to symptoms that develop during or after activity. Before starting this program, it is crucial for the clinician to educate the patient on recognizing perceived exertion and the use of other metrics such as heart rate or exertion scales (such as the Borg Rating of Perceived Exertion Scale) that can guide the individual toward submaximal exertional activities. Smartphones and activity trackers may also be effective methods to monitor duration and intensity of activity. 19 The severity of PASC fatigue can range from mild to severe. Most patients with PASC who have presented to the multidisciplinary clinics report moderate to severe symptoms. There are multiple well-validated measures available to measure fatigue such as the Fatigue Severity Scale, the Fatigue Impact Scale, and the Brief Fatigue Impact Score. 20 Previous literature has defined levels of fatigue in cancer patients on a 10-point scale from 0 ("not present") to 10 ("as bad as you can imagine") with scores of 1-3 representing mild fatigue, 4-6 representing moderate fatigue, and 7-10 representing severe fatigue. 21 In the context of ME/CFS, the National Institute for Health and Care Excellence in their 2007 guidelines define severity of fatigue. 22 Based on our experience, we find these definitions appropriate as a basis for the following classification of PASCrelated fatigue.

• Mild fatigue: Individuals have intact mobility, can perform activities of daily living and do light housework (often with difficulty). They are also able to continue working or going to school but may have stopped other, nonessential activities. They often take time off, require modifications to their schedule, and use weekends to recover from their work week. • Moderate fatigue: Individuals have decreased community mobility and are limited in their performance of instrumental activities of daily living (particularly preparing meals, shopping, doing laundry, using transportation, and performing housework). They require frequent rest periods and naps and have generally stopped work or school. • Severe fatigue: Individuals are mostly confined to the home and may have difficulty with activities of daily living (eating, bathing, dressing, transferring, toileting, mobility). Leaving the home for these individuals is very limited and often leads to prolonged/severe after-effects.

The recommended program depends on the severity of PASC-related fatigue:

• Mild fatigue: We advise patients to continue all household and community activities that have been tolerated with a slow return to higher intensity activities and exercise following the "rule of tens." The "rule of tens" consists of increasing duration, intensity, and frequency of activity/exercise by 10% every 10 days. Using the Rate of Perceived Exertion (RPE) scale, start at RPE 10-11/Light and progressing to 14-15/Hard on resumption of exercise. If patients do not feel comfortable with initiating this program or if gentle resumption of physical activities has previously been tried unsuccessfully, we recommend using the program for moderate fatigue. • Moderate fatigue: We recommend continuation of household and limited community activities that have been tolerated. Patients should begin an activity or aerobic exercise program with exertion at submaximal levels, RPE 9-11/Very Light-Light. The activity or exercise can then be slowly advanced as the patient tolerates as long as it does not cause worsening of symptoms (which may be delayed until the evening and/or days after the activity/exercise session). If symptoms worsen, activity should be returned to the previously tolerated level. Consider referral to a rehabilitation therapist with knowledge of post-COVID care to guide an individually titrated, symptom-guided program. • Severe fatigue or significant PEM: Continue any household activities that have been tolerated without symptom exacerbation. Patients can begin a physical activity program, which should initially consist of upper and lower extremity stretching and light muscle strengthening before any targeted aerobic activity. Once tolerated, patients can begin an activity or aerobic exercise program at submaximal levels, RPE 7-9/Extremely to Very Light. The activity or exercise can then be slowly advanced as the patient tolerates as long as it does not cause worsening of symptoms (which may be delayed until the evening and/or days after the activity/exercise session). If symptoms worsen, activity should be returned to the previously tolerated level. Consider referral to a physician with knowledge of post-COVID care (such as a physiatrist) to guide an individualized T A B L E 3 National Aademy of Sciences proposed diagnostic criteria for ME/CFS Proposed Diagnostic Criteria for ME/CFS Diagnosis requires that the patient has the following three symptoms:

1. A substantial reduction or impairment in the ability to engage in preillness levels of occupational, education, social, or personal activities that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest, 2. Postexertional malaise a and

At least one of the following manifestations is also required: rehabilitation program that may require starting with a home health program for patients with very limited tolerance of community activities.

We also recommend educating patients on energy conservation strategies to aid in recovery. One framework is the "Four Ps": Pacing, Prioritizing, Positioning, and Planning. 23 Pacing is the concept of avoiding the push and crash cycle that is common in post-COVID recovery. Ways to achieve optimal pacing include keeping activity to reasonable, and often shorter, durations (or alternatively, giving more time to complete activities to avoid rushing) and including scheduled rest breaks with activities. Patients should pay attention to their body and avoid or moderate activities that lead to the need for prolonged recovery periods.

Prioritizing encourages a patient to focus and decide on which activities need to get done on specific days and which activities can be postponed (or are unnecessary to do at all) to avoid overexertion and crashing.

Positioning is modifying activities to make them easier to perform. For example, it may be possible for the patient to sit during an activity or have a workspace at a comfortable height with all necessary equipment within easy reach. Another example would be the use of a shower chair or bench rather than standing for showering.

Planning encourages the patient to plan the day or week to avoid overexertion and to recognize energy windows. Energy windows are periods during the day when patients have more energy to complete tasks. Patients are often aware of their optimal energy window, which may vary throughout the week. Asking patients to keep a diary of good days, bad days, and energy windows is helpful for optimizing timing of therapy and activities. As such, it is important for patients to plan rest breaks. Other elements of planning include determining steps for completion of tasks and preparing for tasks ahead of time. Daily routines may also be helpful. Finally, planning may consist of gradual return to previous activities.

In particular, returning to work may be of concern to individuals with PASC-related fatigue. We recommend patients work with their physicians and employers to create a specific plan for return to vocational activities. Patients should be advised on ways to resume work, even if accommodations are needed or in a limited capacity as long as it does not worsen symptoms or lead to significant PEM. Examples of possible accommodations include working a limited number of hours, working from home, adjusting work activities (eg, seated instead of standing/walking activities), using durable medical equipment (eg, mobility aid to increase walking tolerance), providing additional breaks throughout the day, and adjusting the work environment (eg, allowing the patient to park closer). These activities and return to work should be advanced as the patient tolerates. When available, referral to vocational rehabilitation counselor can be helpful in structuring the return activities and communicating with employers.

Encourage patients to follow a healthy dietary pattern and stay hydrated throughout the day At this time there are no scientific data to support the "prescription" of one specific diet for the management of PASC-related fatigue. General nutritional recommendations should reflect the individual patient's underlying comprehensive health profile. General nutrition guidelines suggest a diet including vegetables, fruits, whole grains, healthy fats, fish, poultry, beans and eggs, dairy, and limited intake of red meats. Adequate intake of water and the avoidance of alcohol is also recommended.

Acute symptomatic COVID-19 is associated with a vigorous immune response and PASC has been theorized to be related to persistence of this immune dysregulation. There has been significant interest in the link between proinflammatory states and chronic disease related fatigue. Single nutrients (polyunsaturated fatty acids, antioxidative vitamins [specifically vitamins A, B12, and D], polyphenols, protein/amino acids) and specific diets (whole grains high in fibers, polyphenol-rich vegetables, and omega-3 fatty acid-rich foods) have been suggested to have anti-inflammatory and fatigue-reducing effects, although further confirmatory research is needed. 24 Mast cell activation syndrome with histamine release has also been suggested to play a role in PASC related-fatigue. 25 It is proposed that some individuals may not tolerate histamine present in foods, thought to be a result of reduced activity of the enzyme diamine oxidase, which breaks down histamine leading to an increased amount of histamine in the body and histamine intolerance. Symptoms include headache, asthma, runny or blocked nose, low blood pressure, irregular heartbeat, hives, itching, diarrhea, flushing, and other conditions and are similar to those reported by individuals with PASC. Although there are no current scientific studies supporting the benefit of a low histamine diet (often consisting of limited cheeses, fruit, seafood, nuts, and other foods) in PASC, anecdotal reports have suggested improvement in some individuals. It is worth noting that challenges following low-histamine diets have also been reported.

Some dietary recommendations have been made for individuals with ME/CFS, and similar dietary recommendations may be beneficial for PASC-related fatigue. These include eating little but often -every 3 to 4 hours, eating foods with a low glycemic index (more complex carbohydrates) in order to support stable energy levels, and eating a balanced diet including fruit, vegetables, fish, meat, dairy, nuts, beans, and pulses (eg, legumes). There is currently not sufficient evidence to support the use of specific nutritional supplements to help CFS including multivitamins, B vitamins, magnesium, essential fatty acids (omega-3s), carnitine, or coenzyme Q10.

Fatigue related to autonomic dysfunction in individuals with PASC, specifically postural orthostatic tachycardia syndrome (POTS), can be partially addressed with adequate water and salt intake. 26, 27 Small and frequent meals are better tolerated and diets 26 with high fiber and complex carbohydrates may help reduce blood glucose (sugar) spikes and lessen POTS symptoms.

Fatigue due to muscle atrophy in the context of weight loss is reported in PASC and can be improved with appropriate caloric and protein intake.

There is a wide variation in the use of medications, herbal remedies and supplements to improve PASCrelated fatigue. Some PASC-collaborative clinics do not use pharmacologic agents whereas others use agents when conservative management has been tried and comorbid conditions have been addressed. Further, patients often express interest in and desire for medications and herbal remedies/supplements that may be helpful so knowledge of these agents is needed for appropriate patient counseling.

Supplements that have been suggested to alleviate chronic fatigue in other causes of chronic illness (eg, multiple sclerosis, fibromyalgia, and ME/CFS) include branched-chain amino acids, omega 3 fatty acids, vitamin B12, vitamin C, vitamin D, magnesium, L-carnitine, coenzyme Q10, ginseng, echinacea, and many others. [28] [29] [30] These supplements have been suggested to support the immune system, reduce inflammation, help with healing, and improve fatigue. It is important to note that there was no consensus on the use of these supplements and they should be considered on a caseby-case basis, recognizing the limited scientific evidence. Additionally, there needs to be consideration of the out-of-pocket cost of supplements, the risk of medication interactions, lack of regulation, and possible side effects.

There are several medications that are commonly used for fatigue in other populations (eg, individuals with ME/CFS, cancer, multiple sclerosis, brain injury, and Parkinson disease) that some PASC clinics prescribe for PASC-related fatigue. [31] [32] [33] [34] Specifically, amantadine, modafinil, and methylphenidate have been used by PASC clinics for the treatment of fatigue. [35] [36] [37] [38] Other medications that have been suggested in the treatment of ME/CFS include antivirals/antibiotics/ antiparasitics, antidepressants, cytokine inhibitors, galantamine, glucocorticoid steroids, immunoglobulins, and rituximab. [39] [40] [41] Controlled trials are limited and evidence for these interventions does not exist or is inconclusive. Some of these medications have approval from the Food and Drug Administration for use in other populations with fatigue, but there are currently no clinical trials examining their use in the PASC population. It is important to note that none of these medications were recommended through our consensus process and therefore, should be considered on a case-by-case basis. There also can be adverse side effects and medication interactions with each of these medications that need to be considered prior to prescribing.

The use of acupuncture has also been reported by collaborative patient representative members to improve fatigue. Although there has not been direct evidence to support its use in PASC-related fatigue, there is some preliminary low-quality evidence that supports its use in ME/CFS. 42 

In the context of PASC, it is important to focus on health equity, health disparities, and social determinants of health (SDOH). Along with the following discussion, clinicians are encouraged to reference the Appendix Table: Health Equity Considerations and Examples in Post-Acute Sequelae of SARS-CoV-2 Infection (PASC): Fatigue for guidance about the integration of health equity considerations with the evaluation and treatment of individuals with PASC.

The World Health Organization defines health equity as "the absence of unfair and avoidable or remediable differences in health among population groups defined socially, economically, demographically or geographically." 43 Healthy People 2020 defined a health disparity as "a particular type of health difference that is closely linked with social, economic, and/or environmental disadvantage" and stated that health disparities "adversely affect groups of people who have systematically experienced greater obstacles to health based on their racial or ethnic group; religion; socioeconomic status; gender; age; mental health; cognitive, sensory, or physical disability; sexual orientation or gender identity; geographic location; or other characteristics historically linked to discrimination or exclusion." 44 There has recently been an increased awareness of how SDOH are contributing to health inequities and disparities. SDOH are the "nonmedical factors that influence health outcomes" and involve the "conditions in which people are born, grow, work, live, and age and the wider set of forces and systems shaping the conditions of daily life." 45 For example, the forces and systems can include economic policies, government agendas, and social norms. From an individual's perspective, SDOH includes level of education, socioeconomic status, employment, neighborhood safety and access to nutritious food, and other factors.

To promote high-quality care in individuals with PASC, we need to ensure resources are equitably available for those affected to maintain physical and mental health. Examples of resources include access to information (eg, written and/or oral in a language the individual easily understands or adapted for someone with a disability), goods and services, affordable and timely testing and care, and medical and mental health care that are all tailored to meet the individualized needs of people, especially those from marginalized communities. When policies, programs, and systems that support health are equitable, poor health outcomes can be reduced, health disparities can be prevented, and the whole of society benefits.

Whereas the association between race/ethnicity and health inequity in acute COVID-19 is now well established, the association of inequities with PASC is relatively unexplored. 46 As more data emerge, there will likely be evidence of racial/ethnic health disparities in accessing care and treatment options because of differential loss of health insurance, inequitable distribution of testing, limited clinical and hospital resources, lack of Internet/broadband access, food insecurity, housing insecurity, and differences in workrelated exposures. 46 Symptoms of fatigue may be reported more commonly in female adults and in older age groups. 24 COVID-19 symptoms may be more severe in pregnant women 47 and pregnancy itself (and the postpartum period) is a well-known cause of fatigue because of a host of biologic and behavioral factors. In addition, people who identify with racial or ethnic minority groups may have a baseline level of chronic fatigue that should be considered in the assessment and treatment approach. 48 Racial and ethnic minority groups may also be at a higher risk of chronic diseases that may increase baseline levels of chronic fatigue. For example, individuals with lower socioeconomic status, non-Hispanic Black adults, and Hispanic adults are at higher risk of obesity, which increases the risk of fatigue. 46 Higher body mass index and obesity are also related to more severe consequences of PASC. 49 Finally, those with lower socioeconomic status may not be able to access appropriate treatments. For example, they may not have the ability to get time off from work to apply appropriate pacing recommendations or to access therapy services.

Vulnerable populations encounter a range of barriers to health care linked to demographic and/or socioeconomic factors such as gender, race/ethnicity, education, occupation, and transport. 50 The structural and cultural divide between the academic health care systems and underrepresented minority communities must be bridged by trusted sources that, in many cases, are community organizations. Community organizations that are faith based, nonprofit, civic, social support related, or education focused serve as the foundation of community engagement. 51 Strategies that are culturally appropriate and community competent and consider the nuances of population, community, family, and individual differences have a vital role in reducing health disparities, promoting health equity, and improving population health. Such approaches require a deep understanding of community, consideration of local data-driven approaches, diverse and equitable partnerships across sectors, messaging that resonates with the target audience(s), and the implementation of policies that support the health of all individuals in the United States. 52 Vulnerable populations facing PASC may have little or no health insurance coverage. In addition, debilitating and disabling symptoms interfere with people's ability to work and therefore to generate income for themselves and their dependents. The vulnerable in society have less job security, less flexibility in their roles, and less entitlement to sick pay and occupational health services. 53 To address inequities in care delivery, we recommend assessment and treatment approaches that incorporate telemedicine, including phone calls and virtual visits, as they can be helpful for ongoing follow-up and might lessen the burden on individuals with limited energy from PASC or who have other concerns about in-person visits (eg, the cost of travel, parking, facility fee charges). Virtual visits expanded rapidly during the pandemic and have been noted to be useful in closing access gaps for various populations such as ethnic/ racial minority groups, rural communities, and the elderly. 54 In addition, individuals should be connected to appropriate social services when available, including assistance for other hardships (eg, financial, family illness, bereavement, caregiving) and resources on disability and reasonable accommodations for work or school, and connections to PASC support groups.

PASC-related fatigue affects individuals physically, emotionally, and cognitively. Individuals with PASCrelated fatigue can experience severe disability and frustration. The pathophysiology causing fatigue after COVID-19 still warrants ongoing detailed research to better understand this constellation of symptoms, while acknowledging the cause of fatigue is likely multifactorial and may be specific to the individual. The goal of this PASC Collaborative Consensus Guidance Statement is to create a coordinated and systematic approach to the evaluation and treatment of patients presenting with PASC. The recommendations represent a consensus of large national multidisciplinary collaborative of centers focused on the treatment of individuals with PASC. The recommendations are based on the most current available data, extrapolation from evidence in similar conditions, and the combined clinical experience of treating thousands of patients with PASC-related fatigue.

The content of this Multi-Disciplinary Consensus Guidance Statement was developed in consultation with the AAPM&R PASC Multi-Disciplinary Collaborative, composed of 30 PASC Clinics (www.aapmr.org/PASCguidance) who contributed to the development of the consensus statements via individuals working in their Post COVID/PASC Clinics or from their unique expertise in the assessment and treatment of PASC in their personal, expert capacity. The views and opinions expressed by Collaborative participants are their own and do not reflect the view of any organization. We would also like to acknowledge and extend a special thank you to Kavitha Neerukonda and Michael Graves, AAPM&R, for their relentless efforts in the formation of the PASC Collaborative and directing the constantly evolving aspects of this work. The work of the writing committees is supported exclusively by AAPM&R without commercial support. Legend: This table is included in the Appendix to provide additional information for clinicians who are treating patients for PASC-related fatigue. This is not intended to be a comprehensive list, but rather to provide clinical examples as they relate to health equity, health disparities, and social determinants of health. The literature demonstrates that all marginalized groups face socioeconomic barriers and access to care barriers, though these may or may not be barriers for a specific individual patient. People with intersectional identities (eg, those who identify with more than one underrepresented or marginalized group), often face enhanced levels of bias and discrimination. 

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A phase 3 randomized, placebocontrolled, double-blind, clinical trial of the effect of modafinil on cancer-related fatigue among 631 patients receiving chemotherapy: a University of Rochester Cancer Center Community Clinical Oncology Program Research base study

Modafinil for the treatment of multiple sclerosis-related fatigue

Modafinil for the treatment of daytime sleepiness in Parkinsonxs disease: a double-blind, randomized, crossover, placebo-controlled polygraphic trial

Amantadine for fatigue in multiple sclerosis

Effectiveness of amantadine hydrochloride in the reduction of chronic traumatic brain injury irritability and aggression

Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial

Modafinil: a review of its pharmacology and clinical efficacy in the management of narcolepsy

Methylphenidate treatment of cognitive dysfunction in adults after mild to moderate traumatic brain injury: rationale, efficacy, and neural mechanisms

Interventions for the treatment and management of chronic fatigue syndrome: a systematic review

Chronic fatigue syndrome: is there a role for non-antidepressant pharmacotherapy?

B-lymphocyte depletion in patients with myalgic encephalomyelitis/chronic fatigue syndrome: a randomized, double-blind, placebo-controlled trial

Acupuncture for chronic fatigue syndrome: a systematic review and meta-analysis

Attributes and predictors of long COVID

A systematic review and meta-analysis of data on pregnant women with confirmed COVID-19: clinical presentation, and pregnancy and perinatal outcomes based on COVID-19 severity

The disproportionate impact of COVID-19 on racial and ethnic minorities in the United States

Global pandemics interconnected-obesity, impaired metabolic health and COVID-19

Barriers to health care among adults with minoritized identities in the United States

A framework for mobilizing health care to respond to the community within the COVID-19 pandemic

COVID-19 and racial/ethnic disparities

How to conduct an outpatient telemedicine rehabilitation or prehabilitation visit

A systematic review and meta-analysis of data on pregnant women with confirmed COVID-19: Clinical presentation, and pregnancy and perinatal outcomes based on COVID-19 severity

Gender-affirming care, mental health, and economic stability in the time of COVID-19: A multi-national, cross-sectional study of transgender and nonbinary people

Prehabilitation May Help Mitigate an Increase in COVID-19 Peripandemic Surgical Morbidity and Mortality

How to Conduct an Outpatient Telemedicine Rehabilitation or Prehabilitation Visit

Outpatient Physical, Occupational, and Speech Therapy Synchronous Telemedicine: A Survey Study of Patient Satisfaction with Virtual Visits During the COVID-19 Pandemic

Racial and Ethnic Disparities in COVID-19-Related Infections, Hospitalizations, and Deaths: A Systematic Review

Disparities in Health Care for Black Patients in Physical Medicine and Rehabilitation in the United States: A Narrative Review

Disparities in Health Care for Hispanic Patients in Physical Medicine and Rehabilitation in the United States: A Narrative Review

African American Patient Disparities in COVID-19 Outcomes, A Call to Action for Physiatrists to Provide Rehabilitation Care to Black Survivors

The Disproportionate Impact of COVID-19 on Racial and Ethnic Minorities in the United States

Prisons and COVID-19 Spread in the United States

Epub ahead of print

COVID-19: The Additional Sentence for the Incarcerated. Health Equity

Flattening the Curve for Incarcerated Populations -Covid-19 in Jails and Prisons

Ableism and Quality of Life During the Coronavirus Pandemic

Impact of COVID-19 on people with physical disabilities: A rapid review

Vulnerable Immigrant Populations in the New York Metropolitan Area and COVID-19: Lessons Learned in the Epicenter of the Crisis

Transfusion support and alternatives for Jehovah's Witness patients

Defining and exploring modesty in Jewish American women

Analysis of the causes of moral injury in the outbreak of 2019-nCoV

The effects of Ramadan fasting on activity and energy expenditure

HE-F-23. Mousa HA. Prevention and Treatment of Influenza, Influenza-Like Illness, and Common Cold by Herbal, Complementary, and Natural Therapies